Active substance delivery system

Abstract

The present invention relates to an active substance delivery system, preferably an anti-cancer agent delivery system, comprising one or more active substances included in nanoparticles and a method for producing such a delivery system.

1 - 13 . (canceled) 
     
     
         14 . A method for treating cancer in a human subject comprising administering an active substance delivery system to the human subject, wherein the delivery system comprises:
 (a) nanoparticles comprising:
 (1) 0.05 to 15 wt.-%, based on the total weight of the nanoparticles, of one or more active substances chosen from cancer chemotherapeutic agents, immunomodulatory drugs, antibodies, viruses, vitamins, enzymes, and combinations thereof, 
 (2) 75 to 99.9 wt.-%, based on the total weight of the nanoparticles, of poly(lactic-co-glycolic acid) (PLGA), and 
 (3) optionally, 0.5 to 20 wt.-%, based on the total weight of the nanoparticles, of one or more surface coating materials chosen from chitosan, carboxymethyl chitosan, cellulose, starch, polyethylene glycols (PEG), polyvinyl alcohols, polymers or block co-polymers, dextran, albumin, surfactants, and pullulan;
 wherein the average size of the nanoparticles is in a range of from 100 to 350 nm; and 
 
   (b) optionally, one or more further pharmaceutically acceptable components.   
     
     
         15 . The method of  claim 14 , wherein the weight ratio of (a)(2) to (a)(1) is from 2:1 to 150:1. 
     
     
         16 . The method of  claim 14  comprising the one or more further pharmaceutically acceptable components of (b), wherein the one or more further pharmaceutically acceptable components are chosen from carriers, polymers, surfactants, stabilizers, wetting agents, emulsifiers, antioxidants, pH influencing agents, disintegrants, recrystallization agents, fluxing agents, preservatives, solvents, salts fillers, binders, foamers, defoamers, lubricants, adsorbents for adjusting the osmotic pressure, and buffers. 
     
     
         17 . The method of  claim 14 , wherein the delivery system is prepared by:
 (i) dissolving PLGA in a solvent,   (ii) dissolving one or more active substances in a solvent,   (iii) mixing the solutions of (i) and (ii) together,   (iv) providing a polyvinyl alcohol (PVA) solution,   (v) adding the mixture of (iii) to the PVA solution by injection to produce nanoparticles, wherein amounts of the mixture and the solution are such that a ratio of a least 1 ml of solution per 5 mg of the summed weight of PLGA and the one or more active substances is achieved,   (vi) optionally, evaporating the solvent of (i) and/or (ii),   (vii) purifying the nanoparticles and subsequently dispersing the nanoparticles in a dispersant,   (viii) coating the nanoparticles with one or more surface coating materials, and   (ix) optionally, adding one or more further pharmaceutically acceptable components to the nanoparticles.   
     
     
         18 . The method of  claim 14 , wherein the solvent of (i) and/or the solvent of (ii) comprises acetone, ethyl acetate, a chlorinated solvent, DMSO, a methylated solvent, tetrahydrofuran, a halogenated hydrocarbon, a dioxane, acetonitrile, or a combination thereof and/or the PVA solution of (v) comprises water, ethanol, saline, or a combination thereof and/or the dispersant of (vii) comprises saline, glucose, a surfactant, a pH modifier, water, or a combination thereof. 
     
     
         19 . The method of  claim 14 , wherein the one or more active substances are chosen from:
 chemotherapeutic agents used against a cancer type chosen from gastrointestinal cancer, gastric cancer, colorectal cancer, hepatobiliary or pancreatic cancer, appendix cancer, esophageal cancer, hepatocellular carcinoma, primary peritoneal cancer, ovarian cancer, endometrial cancer, prostate cancer, leukaemia, lymphoma, soft-tissue sarcoma, multiple myeloma, bladder cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, tumours of embryonal origin; and/or   immunomodulatory drugs chosen from curcumin, lutein, hesperidin, apigenin, hesperetin, ajoene, arctigenin, β-carotene, epigallocatechin-3-gallate, glabridin, and quinic acid.   
     
     
         20 . The method of  claim 14 , wherein the method treats a cancer type chosen from gastrointestinal cancer, gynaecological cancer, prostate cancer, peritoneal metastasis, leukaemia, lymphoma, soft-tissue sarcoma, multiple myeloma, breast cancer, bladder cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, ovarian cancer, peritoneal metastasis colorectal cancer, and stomach cancer. 
     
     
         21 . The method of  claim 14 , wherein the method is performed with an assisting tool chosen from microneedles, spray devices, angio-injectors, and a combination thereof. 
     
     
         22 . The method of  claim 14 , wherein a single administration of the delivery system delivers 120 mg to 2500 mg of the one or more active substances to the human subject and/or delivers 30 mg/m 2  body surface to 250 mg/m 2  body surface of the one or more active substances to the human subject. 
     
     
         23 . A method for producing an active substance delivery system comprising:
 (i) dissolving PLGA in a solvent,   (ii) dissolving one or more active substances in a solvent,   (iii) mixing the solutions of (i) and (ii) together,   (iv) providing a polyvinyl alcohol (PVA) solution,   (v) adding the mixture of (iii) to the PVA solution by injection to produce nanoparticles, wherein amounts of the mixture and the solution are such that a ratio of a least 1 ml of solution per 5 mg of the summed weight of PLGA and the one or more active substances is achieved,   (vi) optionally, evaporating the solvent of (i) and/or (ii),   (vii) purifying the nanoparticles and subsequently dispersing the nanoparticles in a dispersant,   (viii) coating the nanoparticles with one or more surface coating materials, and   (ix) optionally, adding one or more further pharmaceutically acceptable components to the nanoparticles.   
     
     
         24 . The method of  claim 23 , wherein:
 the solvent of (i) and/or the solvent of (ii) comprises acetone, ethyl acetate, a chlorinated solvent, DMSO, a methylated solvent, tetrahydrofuran, a halogenated hydrocarbon, a dioxane, acetonitrile, or a combination thereof; and/or   the PVA solution of (v) comprises water, ethanol, saline, or a combination thereof; and/or   the dispersant of (vii) comprises saline, glucose, a surfactant, a pH modifier, water, or a combination thereof.   
     
     
         25 . The method of  claim 23 , wherein the one or more active substances are chosen from:
 chemotherapeutic agents used against a cancer type chosen from gastrointestinal cancer, particularly gastric cancer, colorectal cancer, hepatobiliary or pancreatic cancer, appendix cancer, esophageal cancer, hepatocellular carcinoma, primary peritoneal cancer, ovarian cancer, endometrial cancer, prostate cancer, leukaemia, lymphoma, soft-tissue sarcoma, multiple myeloma, bladder cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, tumours of embryonal origin; and/or   immunomodulatory drugs chosen from curcumin, lutein, hesperidin, apigenin, hesperetin, ajoene, arctigenin, β-carotene, epigallocatechin-3-gallate, glabridin, and quinic acid.   
     
     
         26 . The method of  claim 23  comprising the addition of the one or more further pharmaceutically acceptable components of (ix) to the nanoparticles, wherein the one or more further pharmaceutically acceptable components are chosen from carriers, polymers, surfactants, stabilizers, wetting agents, emulsifiers, antioxidants, pH influencing agents, disintegrants, recrystallization agents, fluxing agents, preservatives, solvents, salts fillers, binders, foamers, defoamers, lubricants, adsorbents for adjusting the osmotic pressure, and buffers.